Challenge with sodium lactate induces panic attacks in individuals who experience clinical panics, but not in normal controls. In terms of both clinical symptoms and response to pharmacotherapy, lactate induced panic attacks appear almost identical to naturally occurring clinical panics, providing researchers with an opportunity to study the mechanisms of a naturally occurring pathological state under laboratory conditions. Previous hypotheses of how lactate infusions precipitate panic--i.e., induction of hypoglycemia, hypocalcemia, alkalosis, peripheral catecholamine surge, beta adrenergic stimulation,--are not supported by findings to date. The data do suggest that lactate induced panics are mediated by central nervous system mechanisms, possibly CO2 hypersensitivity, and may reflect a trait rather than state vulnerability. The present proposal aims to clarify the mechanisms of lactate induced panic by comparative challenges designed to elucidate: a) the relative role and dose effect relationships of L or D lactate as respectively involved in metabolic pathways and physical mechanisms (e.g., calcium chelation); b) the importance of alkalosis (metabolic and respiratory), of increase in brain CO2, and of shift in redox balance; c) and the role of conditioning and anticipatory anxiety. Therefore, comparative trials of 0.5 DL lactate, 0.5M D-lactate, 0.5M L-lactate, bicarbonate, various levels of CO2 inhalation and room air hyperventilation are projected. Comparison of lactate and lactate preceded by acute clonidine and, separately, diazepam pretreatment will investigate, respectively, the possible role of the locus ceruleus in the final discharge pattern for panic and the priming function of anticipatory anxiety for lactate panicogenesis suggested by our studies thus far. Other goals of the current proposal are to see if successful behavioral therapy, like pharmacotherapy, can block lactate induced panic; to develop further objective psychophysiological indices of lactate induced panic; and to study the trait vs state nature of lactate vulnerability and antecedents of relapse by conducting a longitudinal clinical and rechallenge study. The long term significance of this research program lies in its contribution to further understanding the mechanisms of vulnerability to panic attacks, which has relevance for clarifying etiology, treatment, transmission and prevention.